MOLECULAR DETERMINANTS OF HIV HYPERMUTATION ABSTRACT Four human APOBEC3 enzymes have the potential to inhibit HIV-1 infection by inducing G-to-A mutations, and these mutations occur in two different dinucleotide contexts: GG-to-AG (APOBEC3G) or GA-to-AA (APOBEC3D, APOBEC3F, and APOBEC3H). Unexpectedly, only one or the other of these hypermutation signatures is predominant in most HIV-1 sequences from infected patients. This biased mutation distribution implies the existence of a mechanism that prevents APOBEC3 enzymes from targeting HIV-1 simultaneously. We hypothesize that this biased mutation distribution is due to natural variations in the APOBEC3G and APOBEC3H genes and that particular alleles define stronger or weaker antiviral responses against HIV-1. In support of this idea, we have identified genetically linked APOBEC3G and APOBEC3H alleles that undergo differential splicing in different human populations. These data and viral hypermutation analyses indicate that in most patients either APOBEC3G or APOBEC3H haplotype II (but not both enzymes at the same time) has the capability to hypermutate HIV-1. Here, we will further test this hypothesis using a combination of computational and molecular virology approaches. Our studies have the potential to reveal natural strengths and weakness in the human innate immune response and discover the underlying molecular mechanisms.